A phase I study of 7-t-butyldimethylsilyl-10-hydroxycamptothecin in adult patients with refractory or metastatic solid malignancies.

PURPOSE: 7-t-Butyldimethylsilyl-10-hydroxycamptothecin (AR-67) is a novel third generation camptothecin selected for development based on the blood stability of its pharmacologically active lactone form and its high potency in preclinical models. Here, we report the initial phase I experience with i.v. AR-67 in adults with refractory solid tumors. EXPERIMENTAL DESIGN AND METHODS: AR-67 was infused over 1 hour daily five times, every 21 days, using an accelerated titration trial design. Plasma was collected on the 1st and 4th day of cycle 1 to determine pharmacokinetic parameters. RESULTS: Twenty-six patients were treated at nine dosage levels (1.2-12.4 mg/m(2)/d). Dose-limiting toxicities were observed in five patients and consisted of grade 4 febrile neutropenia, grade 3 fatigue, and grade 4 thrombocytopenia. Common toxicities included leukopenia (23%), thrombocytopenia (15.4%), fatigue (15.4%), neutropenia (11.5%), and anemia (11.5%). No diarrhea was observed. The maximum tolerated dosage was 7.5 mg/m(2)/d. The lactone form was the predominant species in plasma (>87% of area under the plasma concentration-time curve) at all dosages. No drug accumulation was observed on day 4. Clearance was constant with increasing dosage and hematologic toxicities correlated with exposure (P < 0.001). A prolonged partial response was observed in one subject with non-small cell lung cancer. Stable disease was noted in patients with small cell lung cancer, non-small cell lung cancer, and duodenal cancer. CONCLUSIONS: AR-67 is a novel, blood-stable camptothecin with a predictable toxicity profile and linear pharmacokinetics. The recommended phase II dosage is 7.5 mg/m(2)/d five times every 21 days.

Dose-escalation study of ICA-17043 in patients with sickle cell disease.

STUDY OBJECTIVE: To determine the dose tolerance, safety, and pharmacokinetics of a single oral dose of ICA-17043 in patients with sickle cell disease. DESIGN: Phase I, randomized, double-blind, placebo-controlled, single-dose, dose-escalation study. SETTING: Four university medical centers. PATIENTS: Twenty-eight patients with sickle cell disease, aged 18-60 years, who were otherwise healthy and in a noncrisis state. INTERVENTION: Patients in three separate dose cohorts--50 mg, 100 mg, and 150 mg--received single doses of ICA-17043 or placebo. MEASUREMENTS AND MAIN RESULTS: The mean area under the concentration-time curve from time zero extrapolated to infinity (AUC(0-infinity)) for ICA-17043 increased in a dose-related manner (11,827, 19,697, and 30,676 ng.hr/ml for 50, 100, and 150 mg, respectively). Overall mean half-life was 12.8 days. Mean peak plasma concentrations rose between the 50- and 100-mg dose levels but plateaued at 150 mg (59.1, 108.7, and 109.1 ng/ml, respectively). Weekly pharmacokinetic and safety assessments were conducted in each patient during the follow-up phase for 56 days. No dose-limiting adverse events were noted in any of the patients. CONCLUSION: Total systemic exposure of ICA-17043 after a single oral dose, as measured by AUC(0-infinity), increased nearly proportionally with the dose. The rate of absorption, however, appeared to be delayed at doses greater than 100 mg. With the long half-life of ICA-17043 demonstrated in this study, once-daily dosing is probably adequate to maintain steady-state plasma concentrations. In addition, single doses of ICA-17043 were well tolerated.